In addition to sucrose which is being most widely employed as a good sweetener, there have been used various sweeteners including sugars such as fructose, isomerized sugars and glucose, sugar alcohols such as sorbitol and mannitol, natural sweetening substances such as glycyrrhizin, stevioside and thaumatin, and artificial sweetening substances such as saccharin sodium, sodium cyclamate, acesulfame-K (3,4-dihydro-6-methyl-1,2,3-oxathiazin-4-one 2,2-dioxide potassium salt), and aspartame.
Recently there have been an increasing number of patients suffering from dental caries as well as obesity, diabetes, cardiopathy, hypertension, renal diseases, etc., which are mainly caused by excessive calorie intake. Thus, it has been required to develop low-calorie sweeteners for the treatment of these diseases or for the maintenance of good health. As the result of attempts for satisfying the above requirement, some products have come into the market. However, artificial sweeteners are strictly regulated because of the toxicity thereof. On the other hand, natural sweeteners are unsatisfactory in sweetness characteristics and aftertaste. In addition, the latter are expensive.
Recently the use of L-aspartyl-L-phenylalanine methyl ester, which will be referred to as aspartame or "APM" hereinafter, has been permitted. This compound is becoming a major artificial sweetener.
There have been reported more than 500 dipeptides including APM (cf. Ariyoshi, Kagaku Sosetsu, No. 14, 85 to 128 (1976); Iwamura, J. Med. Chem., 24, 572 to 583 (1981); and A. Van der Heijden et al., Chemical Senses and Flavor, 4(2), 141 to 152 (1979)). However there are few substances having a degree of sweetness 500 times or more as high as that of sucrose. Further these dipeptides, which are esters, would be hydrolyzed in aqueous solutions or undergo a dealcoholation reaction with an amino group of an aspartate residue to thereby form a diketopiperazine derivative, which would frequently eliminate or alter the sweetness characteristics of the same.
Among dipeptide esters known so far, L-aspartyl-DL-aminomalonic acid methyl fenchyl diester reported by Fujino et al. (cf. JP-B-52-34622, JP-A-49-30566, and Chem. Pharm. Bull., 24(9), 2112 (1976)) has the highest degree of sweetness, though it is inferior to APM in stability at 80.degree. C. and at a pH of 4. (The terms "JP-A" and "JP-B" mean an "unexamined published Japanese patent application" and an "examined Japanese patent publication", respectively.) Recently JP-A-62-30748 has reported that L-aminocarboxylic acid amides of alkyl-substituted cycloalkyls or bicycloalkyl-substituted amino alcohols or aminoketones are 30 to 600 times sweeter than sucrose. Further JP-A-56-127339 has reported branched amides of L-aspartyl-D-amino acid, and U.S. Pat. No. 4,423,029 has reported (S)-3-amino-4-4-oxobutyric acid compounds. However the degrees of sweetness of these compounds are only 200 to 300 times as high as that of sucrose and thus they are not completely satisfactory.